The Groebke-Blackburn-Bienaymé reaction (GBBR) is used for the one-pot synthesis of therapeutically relevant fused imidazoles bridgehead nitrogen heterocyclic compounds from readily available aldehyde, isocyanide and amidine building blocks. The reaction is driven by a wide range of catalysts and can be performed either under solvent or solvent-free conditions, or under microwave irradiation as heat source. The GBBR products can be used for the synthesis of a variety of more complex scaffolds via postmodification reactions. These include cyclization and nucleophilic substitution as well as further MCRs. The GBBR reaction has seen diverse applications in combinatorial and medicinal chemistry and its products are of great use in drug discovery. In this review, we summarize the efforts of the chemistry community in the progress and applications of GBBR since 1998. This review also includes some biological profiles and synthetic scopes of GBBR products. The component variations, postmodifications and secondary transformations will also be discussed throughout this review.
The reaction of benzoyl hydrazine 1a or benzothiazole-2-carbohydrazide 1b with 2-oxo-N-arylpropanehydrazonoyl chlorides 2a-d yielded (1Z,2E)-2-[(benzoyl/benzothiazol-2-oyl)hydrazono]-N-(aryl)propanehydrazonoyl chlorides 3a-e. The reaction of 3a-c with sodium benzenesulphinate furnished sulphones 5a-c while the reaction of 5d, e with hydroxyl amine afforded hydroxomoyl derivatives 6a, b. The one-pot sterioselective reaction of N-(aryl)propanehydrazonoyl chlorides 3 with certain aromatic aldehydes in the presence of piperidine resulted in the formation of (1E,2Z,3E)-1-(piperidin-1-yl)-1-(arylhydrazono)-2-[(benzoyl/benzothiazol-2-oyl)hydrazono]-4-(aryl1)-but-3-enes 7a-g. X-ray analysis of piperidinyl amidrazone 7g showed a conversion of its geometrical structure with respect to that of compound 3 and confirmed the stereoselectivity of the latter reaction. The piperidinyl amidrazones 7a-g possessed a significant antiviral activity against herpes simplex viruses (HSV-1). Compound 7d reduced the number of viral plaques of herpes simplex type-1 (HSV-1) by 67%, with respect to the effect of reference drug Aphidicolin.
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